IFN-γ-induced Cell Autonomous Immunity to Toxoplasma gondii

The relative contribution and efficacy of IFN-γ-inducible antimicrobial effectors varies depending on the intracellular niche occupied by the pathogen, the host species that is infected as well as the pathogen and strain-specific evasion mechanisms.In the case of T. gondii, its unique intracellular niche makes it impervious to antimicrobial mediators that operate strictly within the confines of a phagosome or on free microbes in the cytosol.However, host species have evolved IFN-γ-inducible mechanisms that are capable of acting on T. gondii within its segregated PV [11].T. gondii has countered this, in part, by evolving a yet undefined mechanism to disrupt chromatin remodeling of STAT1 regulated promoters in infected cells; resulting in suppression of greater than 60% of IFN-γ induced transcripts [12][13][14].Consequently, anti-T.gondii effector activity can differ depending on whether host cells are activated prior versus after parasite invasion.However, parasite downregulation of inducible nitric oxide synthase (iNOS) is not necessarily sufficient to avoid growth arrest by the residual nitric oxide (NO) produced even in infected cells and this may hold true for other antimicrobial effectors as well [15].IFNγ-inducible indoleamine 2, 3-dioxygenases (IDOs) mediate anti-T.gondii activity by restricting intracellular access to tryptophan; T. gondii is a tryptophan auxotroph [16,17].IFN-γ-induced gasses such as reactive nitrogen (RNS) and oxygen species (ROS) are ancient and relatively conserved anti-microbial agents that can disrupt function of multiple processes in a microbe simultaneously and have the added benefits of acting synergistically and of being highly diffusible to enable contact with pathogens in diverse intracellular niches.In the case of T. gondii, inducible ROS generated predominantly by NADPH oxidase are capable of anti-T.gondii activity [18][19][20] during infection in both humans and mice.Similarly, nitric oxide generated by iNOS suppresses parasite replication independent of parasite genotype [21-